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Daniel Boakye, Viola Walter, Lina Jansen, Uwe M. Martens, Jenny Chang-Claude, Michael Hoffmeister, and Hermann Brenner

Background: Comorbidities and old age independently compromise prognosis of patients with colorectal cancer (CRC). The impact of comorbidities could thus be considered as conveying worse prognosis already at younger ages, but evidence is lacking on how much worsening of prognosis with age is advanced to younger ages in comorbid versus noncomorbid patients. We aimed to quantify, for the first time, the impact of comorbidities on CRC prognosis in “age advancement” of worse prognosis. Methods: A total of 4,602 patients aged ≥30 years who were diagnosed with CRC in 2003 through 2014 were recruited into a population-based study in the Rhine-Neckar region of Germany and observed over a median period of 5.1 years. Overall comorbidity was quantified using the Charlson comorbidity index (CCI). Hazard ratios and age advancement periods (AAPs) for comorbidities were calculated from multivariable Cox proportional hazards models for relevant survival outcomes. Results: Hazard ratios for CCI scores 1, 2, and ≥3 compared with CCI 0 were 1.25, 1.53, and 2.30 (P<.001) for overall survival and 1.20, 1.48, and 2.03 (P<.001) for disease-free survival, respectively. Corresponding AAP estimates for CCI scores 1, 2, and ≥3 were 5.0 (95% CI, 1.9–8.1), 9.7 (95% CI, 6.1–13.3), and 18.9 years (95% CI, 14.4–23.3) for overall survival and 5.5 (95% CI, 1.5–9.5), 11.7 (95% CI, 7.0–16.4), and 21.0 years (95% CI, 15.1–26.9) for disease-free survival. Particularly pronounced effects of comorbidity on CRC prognosis were observed in patients with stage I–III CRC. Conclusions: Comorbidities advance the commonly observed deterioration of prognosis with age by many years, meaning that at substantially younger ages, comorbid patients with CRC experience survival rates comparable to those of older patients without comorbidity. This first derivation of AAPs may enhance the empirical basis for treatment decisions in patients with comorbidities and highlight the need to incorporate comorbidities into prognostic nomograms for CRC.

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Melissa S.Y. Thong, Daniel Boakye, Lina Jansen, Uwe M. Martens, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, and Volker Arndt

Background: Colorectal cancer (CRC) survivors generally have a higher healthcare utilization (HCU) than the general population due to cancer burden. However, it is unclear which factors are associated with this increased uptake. Our study aimed to (1) compare CRC-related and non-CRC visits to general practitioners (GPs) and medical specialists (MSs) by comorbidities, and (2) assess whether HCU differs by demographic, clinical, and psychological factors. Methods: We used data from a German population-based cohort of 1,718 survivors of stage I–III CRC diagnosed in 2003 through 2010 who provided information on HCU at 5-year follow-up. Multivariable linear regression was used to calculate least-square means of CRC-related and non-CRC HCU according to the Charlson comorbidity index and comorbidity cluster, adjusting for relevant demographic, clinical, and psychological characteristics. Results: A higher comorbidity level was associated with more CRC-related MS visits and non-CRC GP visits. In addition to being strongly associated with non-CRC GP visits, comorbidity clusters were associated with CRC-related GP and MS visits, but their association varied by specific cardiometabolic comorbidities. HCU was less dependent on prognostic factors for CRC, such as age and tumor stage, but was strongly associated with disease recurrence, depression, and emotional functioning. Conclusions: Comorbidities, rather than age or tumor stage, were related to HCU, suggesting that CRC survivors use healthcare mainly for reasons other than cancer 5 years postdiagnosis. Improved communication between primary and tertiary healthcare providers could enhance the medical care of cancer survivors with complex health needs and thereby also reduce healthcare costs.

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Yu Tian, Elham Kharazmi, Hermann Brenner, Xing Xu, Kristina Sundquist, Jan Sundquist, and Mahdi Fallah

Background: The aim of this study was to explore the risk of invasive colorectal cancer (CRC) in relatives of patients with colorectal carcinoma in situ (CCIS), which is lacking in the literature. Patients and Methods: We collected data from Swedish family-cancer datasets and calculated standardized incidence ratio (SIR) and cumulative risk of CRC in family histories of CCIS in first- and second-degree relatives. Family history was defined as a dynamic (time-dependent) variable allowing for changes during the follow-up period from 1958 to 2015. Of 12,829,251 individuals with available genealogical data, 173,796 were diagnosed with CRC and 40,558 with CCIS. Results: The lifetime (0–79 years) cumulative risk of CRC in first-degree relatives of patients with CCIS was 6.5%, which represents a 1.6-fold (95% CI, 1.5–1.7; n=752) increased risk. A similarly increased lifetime cumulative risk (6.7%) was found among first-degree relatives of patients with CRC (SIR, 1.6; 95% CI, 1.6–1.7; n=6,965). An increased risk of CRC was also found in half-siblings of patients with CCIS (SIR, 1.9; 95% CI, 1.1–3.0; n=18) and also in half-siblings of patients with CRC (SIR, 1.7; 95% CI, 1.3–2.1; n=78). Moreover, the increased risk of CRC was higher for younger age at diagnosis of CCIS in the affected first-degree relative and for younger age at diagnosis of CRC in the index person. Conclusions: Results of this study show that first-degree relatives and half-siblings of patients with CCIS have an increased risk of CRC, which is comparable in magnitude to the risk of those with a family history of invasive CRC. These findings extend available evidence on familial risk of CRC and may help to refine guidelines and recommendations for CRC screening.

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Ruth Elisa Eyl-Armbruster, Melissa S.Y. Thong, Prudence R. Carr, Lina Jansen, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, and Volker Arndt

Background: Little is known about how changes in a constellation of lifestyle factors affect health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. Our study aimed to investigate the association between changes in healthy lifestyle and HRQoL over time in survivors of stage I–IV CRC. Methods: We included 2,283 long-term (≥5 years postdiagnosis) survivors. A healthy lifestyle score (HLS) comprising smoking, alcohol consumption, diet, physical activity, and body fatness was derived at diagnosis and 5-year follow-up (5YFU) and categorized as low, moderate, or high. We assessed HRQoL with the EORTC Quality of Life Questionnaire-Core 30 at 5YFU and 10-year follow-up. We used multivariable linear regression and linear mixed models to explore associations between changes in HLS and HRQoL over follow-up. Results: A low baseline HLS was associated with poorer functioning and global health/QoL and a higher symptom burden at 5YFU compared with a high baseline HLS. An improved HLS from baseline to 5YFU was associated with better functioning, higher global health/QoL, and fewer symptoms at 5YFU than a maintained-high HLS. In longitudinal analyses, improved HLS was associated with better functioning at follow-up. Survivors with a maintained-high or an improved HLS reported generally less fatigue, pain, and dyspnea at follow-ups compared with survivors with a maintained-low or decreased HLS. Conclusions: Change toward a healthier lifestyle since diagnosis was associated with better HRQoL in long-term CRC survivors. Our results support the importance of maintaining and/or promoting a healthier lifestyle among CRC survivors postdiagnosis.

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Lina Jansen, Daniel Boakye, Elizabeth Alwers, Prudence R. Carr, Christoph Reissfelder, Martin Schneider, Uwe M. Martens, Jenny Chang-Claude, Michael Hoffmeister, and Hermann Brenner

Background: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany. Methods: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively. Results: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I–III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20–4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis. Conclusions: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.

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Viola Walter, Daniel Boakye, Janick Weberpals, Lina Jansen, Walter E. Haefeli, Uwe M. Martens, Phillip Knebel, Jenny Chang-Claude, Michael Hoffmeister, and Hermann Brenner

Background: Chemotherapy underuse in elderly patients (aged ≥75 years) with colon cancer has been reported in previous studies. However, these studies were mostly registry-based and limited in their potential to consider underlying reasons of such undertreatment. This study aimed to evaluate patient and hospital determinants of chemotherapeutic treatment in patients with stage III colon cancer, with a particular focus on age and underlying reasons for nontreatment of elderly patients. Methods: A total of 629 patients with stage III colon cancer who were diagnosed in 2003 through 2012 and recruited into a population-based study in the Rhine-Neckar region of Germany were included. Information on sociodemographic and lifestyle factors, comorbidities, and treatment was collected from patient interviews and physicians. Patient (with an emphasis on age) and hospital factors were evaluated for their associations with administration of adjuvant chemotherapy overall and of oxaliplatin specifically using multivariable logistic regression. Results: Administration of chemotherapy decreased from 94% in patients aged 30 to 64 years to 51% in those aged ≥75 years. A very strong decline in chemotherapy use with age persisted even after comprehensive adjustment for multiple patient factors—including comorbidities—and hospital factors and was also seen among patients without any major comorbidities. Between 2005 and 2008, and 2009 and 2012, chemotherapy administration in patients aged ≥75 years decreased from 60% to 41%. Among chemotherapy recipients, old age was also strongly associated with higher odds of nonadministration of oxaliplatin. The 2 most commonly reported reasons for chemotherapy nonreceipt among the study population were patient refusal (30%) and old age (24%). Conclusions: Age was the strongest predictor of chemotherapy underuse, irrespective of comorbidities and even in patients without comorbidities. Such underuse due just to older age in otherwise healthy patients deserves increased attention in clinical practice to ensure that elderly patients also get the best possible care. Patients’ refusal as the most frequent reason for chemotherapy nonreceipt also warrants further investigation to exclude misinformation as underlying cause.